Tau pathology is a prominent feature of the diseases known as tauopathies including Alzheimer?s disease (AD) and Alzheimer?s Disease Related Dementias (ADRDs), i.e. Progressive Supranuclear Palsy (PSP), Cortical Basal Degeneration (CBD), Pick?s disease (PiD), Frontotemporal Dementia (FTD) and Chronic Traumatic Encephalopathy (CTE). Some diseases are due to mutations in tau, but normal tau is pathological in AD or CTE. Each tauopathy has a disease specific phenotype, histological presentation, morphology and clinical presentation, but all exhibit hyperphosphorylation and misfolding of tau. This suggests a common pathogenic mechanism. Our central hypothesis is that pathogenic forms of tau represent misregulation of a normal biological function for tau as a scaffold for localization and regulation of microtubule-based kinases and phosphatases. Our discovery of a biologically active motif in tau that activates protein phosphatase 1 (PP1) and glycogen synthase kinase 3b (GSK3b) may reflect a common molecular basis for increased kinase activities in tauopathies. Exposure of 17 amino acids comprising a Phosphatase Activation Domain (PAD) is normally restricted, but becomes constitutive in pathological forms of tau. PAD is aberrantly displayed in all pathological forms of tau examined to date and is a component of tau toxicity of patient-derived tau aggregates. Recent studies show that specific tau phosphorylations can spatially and temporally regulate PAD exposure and that tau interacts with PP1 and GSK3b. Pathological tau in different tauopathies is structurally distinct and exhibit variable degrees of toxicity. These variations may reflect differences in tau isoforms, post- translational modifications, and mutations. We will characterize the physiological roles of tau in normal brain as well as AD and ADRDs. Normal and pathological functions of tau will be analyzed to test the hypothesis that tau serves as a scaffold for localizing and regulating specific kinases and phosphatases to microtubules. Aim 1 will characterize the role of tau in normal regulation of PP1 and GSK3b in axonal domains. We propose that presentation of PAD is restricted to specific subcellular compartments in normal neurons and deregulated in pathological states. Numerous posttranslational modifications (PTMs) of tau in normal and diseased brains suggest a role in tau function and Aim 2 will identify functional consequences of specific PTMs. We propose that toxicity of pathological tau may be modulated by disease specific patterns of tau PTMs, splice isoforms and mutations that affect tau conformation. Experiments in Aim 3 will determine the physiological significance of different splice forms of tau in affecting presentation of PAD and other biologically active motifs in tau. Finally, Aim 4 will evaluate how mutations in tau may lead to differential exposure of PAD and other motifs. Developmental regulation of tau isoforms and PTMs may play critical roles in both neuronal development and pathogenesis in AD and ADRDs. Regulated presentation of PAD is important for neuronal function, while aggregation, PTMs and mutations disrupt normal regulation of PAD.